Description: (Applicant's Description) Apoptosis, a form of programmed cell death, is the major mechanism whereby chemotherapy and radiation kill cancer cells. Compared to normal cells, cancer cells are resistant to apoptosis due to the activity of anti-apoptosis signaling pathways. The hypothesis upon which Project 3 of the NCDDG is based is that restoring sensitivity to apoptosis through the use of drugs that inhibit key components of apoptosis resistance signaling pathways offers a novel way of selectively killing cancer cells and of improving their sensitivity to current therapies. The objective of the work is to use validated anti-apoptosis targets in cancer cells for the discovery new types of agents that will selectively promote apoptosis in cancer cells. Project 3 will focus on three major apoptosis resistance pathways as targets for its anticancer drug discovery efforts. They are: 1) redox signaling through the anti-apoptosis proto-oncogene protein thioredoxin; 2) activation of NF-KB; and, 3) the PTEN/Akt signaling pathway. Molecular and pharmacologic proof-of-principle that each of these are rational and tractable targets for anticancer drug discovery is provided. A hierarchical series of robust screening assays for discovering lead compounds from a large chemically diverse library and for lead optimization through the use of combinatorial chemistry in collaboration with other components of the NCDDG is proposed. A series of secondary assays and gene expression arrays will be used to assess selectivity and selected and engineered cancer cell lines will be used for testing of the compounds. The goal of the project is to identify each year for each of the targets a number of compounds for preclinical testing.